Practical example of scaling up a biotech process using ...
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Practical example of scaling up a biotech process using QTPPs, CQAs and CPPs Presented by Michelle Edmonds 4 July, 2016
Transcript of Practical example of scaling up a biotech process using ...
Practical example of scaling up a biotech process using QTPPs, CQAs and CPPsPresented by Michelle Edmonds
4 July, 2016
Slide 2 © PharmOut 2015
Project objectives
• Manufacture of PharmOtein
• Parenteral protein solution
• Scale up of the manufacturing process from pilot scale (10 L
batch size) to production scale (100 L batch size)
• Design and specification of the process equipment
Slide 3 © PharmOut 2015
Process validation lifecycle
Stage 2
Process Qualification
Stage 1
Process Design
Stage 3
Continued ProcessVerification
Evaluate / Confirm
Distribute
Design of Facilities & Qualification of Equipment and
Utilities
Process Performance Qualification
(PPQ)
Stage 3a
Heightened sampling & testing
until variability understood
Stage 3b
Routine monitoring program
Commercial Manufacturing
FDA Product Life Cycle – Process Validation
Changes
Slide 4 © PharmOut 2015
Manufacturing process scale-up
Define the Quality Target Product Profile
(QTPP)
Identify the CQAs
Define process steps & CPPs
Create a control strategy
Stage 1
Implement the control strategy
Qualify Facility, Utilities,
Systems and Equipment
Process Validation
(PPQ)
ContinuedProcess
Verification
Stage 2
Stage 3
Create process map
Identify process steps & operating parameters
Slide 5 © PharmOut 2015
PharmOtein manufacturing process
Bulk PharmOtein
Clarification Diafiltration Formulation Sterile filling
Identify process steps & operating parameters
Slide 6 © PharmOut 2015
Quality target product profile (QTPP)
“A prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the
desired quality, taking into account safety and efficacy of the drug product”.
(ICH Q8)
Define the quality target product profile
(QTPP)
Slide 7 © PharmOut 2015
Quality target product profile (QTPP)
Attribute* QTPP
Dosage volume 10 mL
Dose 100mg
Particulates No visible particles
Chemical purity pH 6.5 – 7.0Excipient ≤0.1%Solutes concentration
Biological purity Meets pharmacopeia requirements for parenteral dosage forms
Aggregate ≤1%
*Only a few PharmOtein QTPPs described here
Example: 100mg PharmOtein vial
Define the Quality Target
Product Profile (QTPP)
Slide 8 © PharmOut 2015
Critical Quality Attributes (CQA)
“A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality”.
(ICH Q8)
Identify the CQAs
Slide 9 © PharmOut 2015
From QTPP to CQAs
Attribute PharmOtein QTPP* Translation to CQA
Dosage volume 10 mL Fill volume
Dose 100mg PharmOtein Concentration
Particulates No visible particles No observed visible particles
Chemical purity pH 6.5 – 7.0Excipient ≤0.1%Solutes concentration
pHExcipient concentrationNaCl concentration
Biological purity Meets pharmacopeia requirements for parenteral dosage forms
Sterility
Aggregate ≤1% Aggregate concentration
Example: 100mg PharmOtein vial
*Only a few PharmOtein QTPPs & CQAs discussed here
Identify the CQAs
Slide 10 © PharmOut 2015
Process step impact
CQA Clarification Diafiltration Formulation Sterile filling
Fill volume
PharmOtein concentration
Visible particles
pH
Excipient concentration
NaCl concentration
Sterility
Aggregate concentration
Known or potential impact to CQADefine
process steps & CPPs
Slide 11 © PharmOut 2015
Identify Operating Parameters
Operating Parameter* Value
Volume for diafitration 1000 L
Volume after concentration 100 L
Mixer speed 200 rpm
Buffer flowrate ~10 L/min
Feed pressure 120 kPag
Temperature Ambient
Feed flowrate 100 L/min
Permeate flowrate ~10 L/min
Permeate pressure 10 kPag
Transmembrane pressure 100 kPag
Diafiltration volume: 10
Duration < 20 hr
pH of solution 6.5 - 7.5
Final concentration 10 ± 0.5 mg/mL
NaCl concentration 100 ± 1 mmol/mL
Example: Diafiltration
*Only a few PharmOtein parameters discussed here
Identify process steps & operating parameters
Slide 12 © PharmOut 2015
Process map - Diafiltration
Create process map
Slide 13 © PharmOut 2015
Parameter definitions
CPP Critical Process Parameter
• A process parameter whose variability impacts a quality attribute and therefore needs to be controlled to ensure the process produces the desired quality.
• A critical process parameter remains critical even if it is controlled.
KOP Key Operating Parameter
A process parameter whose variability affects the desired operability of the system or equipment to produce the desired output but has no impact on a quality attribute.
NOP Normal Operating Parameter
A process parameter whose variability has no impact on the desired operability of the system or equipment to produce the desired output as well as a quality attribute.
Define process steps & CPPs
Slide 14 © PharmOut 2015
Defining CPPs, KOPs, NOPs
Process Parameter
Potential Impact to
CQAs?
NOYESPotentially
a CPPPotentially NOT a CPP
CriticialityAssessment.
CPP?
YESCPP
NOKOP
NOP
OR
Define process steps
& CPPs
Slide 15 © PharmOut 2015
The PharmOut “STIC-man”
Summary Table from Ishikawa Criticality-man!
Define process steps
& CPPs
Slide 16 © PharmOut 2015
Define parameters
Operating Parameter* Value Parameter Type
Volume for diafiltration 1000 L NOP
Volume after concentration 100 L CPP
Mixer speed 200 rpm KOP
Buffer flowrate ~10 L/min KOP
Feed pressure 120 kPag KOP
Temperature Ambient KOP
Feed flowrate 100 L/min KOP
Permeate flowrate ~10 L/min KOP
Permeate pressure 10 kPag NOP
Transmembrane pressure 100 kPag KOP
Diafiltration volume: 10 CPP
Duration < 20 hr NOP
pH of solution 6.5 - 7.5 CQA
Final PharmOtein concentration 10 ± 0.5 mg/mL CQA
NaCl concentration 100 ± 5 mmol/mL CQA
Example: 100mg PharmOtein vial, Diafiltration
*Only a few PharmOtein parameters discussed here
Define process steps
& CPPs
Slide 17 © PharmOut 2015
Control strategy
“A planned set of controls, derived from current product and process understanding that ensures process performance
and product quality.”
(ICH Q10)
Create a control strategy
Slide 18 © PharmOut 2015
Control strategy
• Will ensure that the process remains in control
• Encompasses all elements of each unit operation of the manufacturing process
• All product attributes and process parameters should be in a complete Process Control Strategy
• Only CPPs require validation and should lead to deviations during production
Create a control strategy
Slide 19 © PharmOut 2015
Control strategy
Parameter Parameter Type
Specification Control
Diafiltration volume CPP 10 >10
Buffer NaClconcentration
CPP 95 – 105 mmol/mL 99 – 101 mmol/mL
Feed flowrate KOP N/A 90 – 110 L/min
Transmembranepressure
KOP N/A 95 – 105 kPag
Permeate flowrate KOP N/A 8 – 12 L/min
Final PharmOteinconcentration
CQA 9.5 – 10.5 mg/mL 9.8 – 10.2 mg/mL
* Only a few PharmOtein parameters included here
Example: Diafiltration
Create a control strategy
Slide 20 © PharmOut 2015
Process design completion
Stage 1 output should be a Report that justifies the Control Strategy:
• Defined CQAs, CPPs and other parameters
• Risk Assessments
• Process Information (Inputs & Outputs)
• Parameters and Ranges
Slide 21 © PharmOut 2015
Process validation lifecycle
Stage 2
Process Qualification
Stage 1
Process Design
Stage 3
Continued ProcessVerification
Evaluate / Confirm
Distribute
Design of Facilities & Qualification of Equipment and
Utilities
Process Performance Qualification
(PPQ)
Stage 3a
Heightened sampling & testing
until variability understood
Stage 3b
Routine monitoring program
Commercial Manufacturing
FDA Product Life Cycle – Process Validation
Changes
Slide 22 © PharmOut 2015
Thank you for your time.Questions?
Michelle Edmonds
Senior Consultant
www.pharmout.net
